Nearly 100 million people in the world, including -57 million in Bangladesh and -15 million in the US, are chronically exposed to inorganic arsenic, a class I human carcinogen, and are at increased risk of skin and other arsenic-induced cancers. As part of an ongoing prospective cohort study, the investigators of this application assembled 11,746 men and women, including nearly 3,575 patients with premalignant skin lesions, and collected questionnaires, clinical data, and biospecimens from all. In addition, ICDDR, B, the Centre for Health and Population Research - an internationally renowned public health research center based in Bangladesh, who are conducting several projects relating to arsenic exposure in a similar study area in Matlab, Bangladesh, have identified approximately 3,421 patients with skin lesions. Columbia University and ICDDR, B will combine their research efforts for the proposed trial thus increasing the number of potential eligible patients to 6,996 patients. We propose to conduct a 2x2 factorial, double-blinded, randomized, placebo-controlled trial among 4,444 of these patients (4,000 with complete follow-up data assuming 10% attrition) to investigate whether vitamin E and/or selenium has a beneficial effect. Although little is known about the development of skin hyperkeratosis and its progression to skin cancer among arsenic-exposed populations, oxidative stress mediated mechanisms are considered to play a major role. Inorganic arsenic has been shown to produce reactive oxygen species (ROS) such as 8-OHdG (8-Hydroxy-2'-deoxyguanosine) which may lead to the development of cancer by introducing mutations in cancer causing genes. Antioxidants, such as vitamin E and selenium may impede the carcinogenic effects of ROS in arsenic-exposed populations. We hypothesize that supplementation with vitamin E and/or selenium has an impact on changes of premalignant skin lesions and its progression to skin cancer and/or on levels of the oxidative DMA damage marker 8-OHdG. The patients will be randomized into four arms (vitamin E vs. selenium vs. vitamin E and selenium, and placebo). The randomization will be stratified based on study site, baseline smoking and arsenic exposure status. Questionnaire and clinical assessment data as well as biospecimen samples (blood and urine) will be collected at baseline and at 3 (36 months), and 5 (60 months) years of follow-up. Mononuclear cell 8-OHdG, serum vitamin E, selenium and carotenoid, and urinary arsenic will be measured at these three visits. In addition, clinical examination data on skin and other cancers will be collected at 1 (12 months), 2 (24 months) and 4 (48 months) years of follow-up. Linear regression and ANOVA will be used to assess the treatment effects on the changes in the 8-OHdG and extent of skin lesions, over the 60- month (5-year) intervention period. Cox's proportional hazards regression model will be used to assess the treatment effects on the incidence of new skin lesions and skin cancer among these patients over the 5-year study period. All analyses, adopting intention to treat principle, will be adjusted for study site, smoking status, plasma carotenoid levels, and arsenic exposure, as well as any other confounders in the data. The results of this randomized clinical trial will provide data on potential low-cost interventions for reducing the cancer risk among millions of arsenic exposed population in Bangladesh and probably other parts of the world. [unreadable] [unreadable]